The incidence of affective disorders including depression and anxiety disorders in women is twice that of men. This gender difference, which emerges during puberty, suggests a potential role of estradiol. Interestingly, the severity of affective symptoms is negatively correlated with the endogenous estradiol levels. However, the mechanism by which endogenous estradiol modulates synaptic circuits relevant to affective behaviors is not well understood. We propose to investigate whether and how variations in estradiol levels modulate synapses in the medial prefrontal cortex (mPFC), a brain region critical for the regulation of affective behaviors. We will also test whether pharmacological activation of estrogen receptors improves affective behaviors during periods of low endogenous estradiol. Preliminary results indicate that the effects of estradiol on the mPFC synapses require brain derived neurotrophic factor (BDNF), a secreted trophic protein involved in affective behaviors. Experiments will be carried out to elucidate the mechanism by which estradiol and BDNF interact at mPFC synapses. These experiments are likely to shed light on the mechanism of sex differences in affective behaviors and the vulnerability of periods of low estradiol levels to environmental and genetic challenges. In addition, our studies will provide insights into possible therapeutic targets and windows of opportunity to modulate the mPFC synapses for the management of affective disorders.